An early start for the thinking brain

The cerebral cortex, a layer of cells just a few millimeters thick on the outermost surface of the brain, is largely what makes humans noble in reason and infinite in faculties. New research from the School of Medicine shows that developing embryos, in their haste to become quintessentially human, generate the first neurons of the cortex only 31 days after fertilization—much earlier than previously thought.

The cerebral cortex is an evolutionary marvel. Its distinctive convoluted shape arose because the size of the cortex expanded disproportionately in relation to the rest of the brain during evolution. The 20 billion neurons packed within the cortex’s smooth gray folds account for about 40 percent of the brain’s weight, and the connections among them are largely responsible for the functions considered unique to humans, such as memory, thought, perceptual awareness, language, intellect and consciousness.

Using precise cellular markers, Pasko Rakic, M.D., Ph.D., the Dorys McConnell Duberg Professor of Neurobiology and professor of neurology, and chair of neurobiology and colleagues have discovered “predecessor” neurons that first appear in human embryos before the neural tube, the precursor of the central nervous system, has completely closed and before eyes, arms and legs begin to bud. According to Rakic, these predecessors could well be one type of neural stem cell of the “thinking brain.”

Until recently, researchers thought that all cortical neurons arose within a rudimentary cortical nexus and then migrated radially, like spokes jutting out from an axle, into place. However, Rakic’s findings show that the predecessor neurons arise from basal layers within the developing brain and then travel through inner cell layers to reach the cortex. The precocious cells generate long extensions that pull them to different locations as the brain develops. These extensions may also act as scaffolds to guide late-blooming cortical neurons to their proper locations.

In the July issue of Nature Neuroscience, the researchers wrote that studying how predecessor cells help to wire the billions of neurons of the adult human cortex may provide new insights into how humans differ from more primitive species and may shed light on the causes of mental illness. “Unraveling the early development of this complex structure,” the team wrote, “might provide the key to understanding both the mechanisms underlying its expansion during evolution and the pathogenesis of many cognitive disorders.” Rakic added, “If we want to repair the human brain, we have to know how the human cortex develops; we have to know the timing, the sequence and the type of cells involved.”

Rakic said that the next goal is to determine which genes are switched on in predecessor cells to control early cortex development. If the predecessors are indeed neural stem cells, identifying the genes responsible for early cortex formation could provide insight into ways to generate new cortical neurons to repair brain injury. The team also plans to identify the source of predecessor cells by performing experiments in nonhuman primates that will enable them to visualize neuron migration using modern microscopy techniques.

These findings will bring researchers one step closer to understanding the developmental mechanisms responsible for creating the thinking brain. “I am fascinated with the idea that I use my cortex to look at the cortex itself to determine what makes it possible for me to think,” said Rakic.

The project, supported by the Kavli Institute for Neuroscience at Yale, involves collaborations with societies in England and Russia.